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Objective: Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients. Methods: In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R). Results: NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12–0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO‐ACT (Pooled Resource Open‐Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS‐R progression was evident independently of disease stages. Notably, NIMV benefits were not dose‐dependent but were particularly prominent for nighttime respiratory support. Interpretation: NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS‐R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV‐induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024;95:817–822 [ABSTRACT FROM AUTHOR]

Recently, pathogenic expansions (range 40–64 CAG repeats) in the HTT gene have been found in patients diagnosed with pure frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). We report a mother with Huntington's disease (HD) associated with motor neuron disease (MND) signs and her daughter suffering from ALS with subtle signs of HD, both carrying a pathogenic allele of the HTT gene (i.e., >39 repeats). The co‐occurrence of MND and chorea has been reported in previous cases. Subjects showing both ALS and HD signs and carrying HTT pathogenic expansions in two generations of the same kindred have never been reported so far. The study of the overlap of disease mechanisms at the cellular level between TDP‐43 and Huntingtin is relevant in an era offering promising strategies of targeted treatments in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies., Competing Interests: Declaration of interests T.G.B. is a consultant for Aprinoia Therapeutics, Vivid Genomics, and Avid Radiopharmaceutical and is a scientific advisory board member for Vivid Genomics. J.A.H., H.R.M., B.J.T., and H.R.M. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. B.J.T. and S.W.S. receive research support from Cerevel Therapeutics. B.J.T. is an editorial and advisory board member for Brain, eClinicalMedicine, Journal of Neurology, Neurosurgery, and Psychiatry, and Neurobiology of Aging. H.R.M. reports paid consultancy from Biogen, Biohaven, Lundbeck, UCB, and Denali as well as lecture fees and honoraria from the Wellcome Trust and the Movement Disorders Society. H.R.M. received research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, the Drake Foundation, and the Medical Research Council. H.K. is editor-in-chief of Clinical Autonomic Research, serves as principal investigator (PI) of a clinical trial sponsored by Biogen MA Inc. (TRACK MSA, S19-01846), and received consultancy fees from Lilly USA LLC, Biohaven Pharmaceuticals Inc., Takeda Pharmaceutical Company Ltd., Ono Pharma UK Ltd., Lundbeck LLC, and Theravance Biopharma US Inc. A.F. reports royalties from Springer Verlag; speaker fees and honoraria from Theravance Biopharma, GE Health Care, Broadview Ventures, Austrian Autonomic Society, Stopp-HSP, and Elsevier; and research grants from the FWF-Austrian Science Fund, Medical University of Innsbruck, US MSA Coalition, Dr. Johannes and Hertha Tuba Foundation, and Austrian Exchange Program, outside of the present work. J.-A.P. is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. I.B. received consultancy fees from Theravance Biopharma US Inc., Amenal Pharmaceutics, Regeneron Pharmaceuticals, Takeda Pharmaceuticals, and Neurawell Therapeutics. S.W.S. serves on the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. is an editorial board member for the Journal of Parkinson’s Disease and JAMA Neurology. A.P. serves on the board of directors for CurePSP, has received research grants from the National Institutes of Health and the Michael J. Fox Foundation, and has received consultancy fees from AbbVie Inc., Biogen Inc., SciNeuro Pharmaceuticals, Ono Pharma, and Ferrer Internacional, S.A. A.T. serves on the scientific advisory board for Vivid Genomics. R.H.R. is currently employed by CoSyne Therapeutics; all work performed for this publication was performed on her own time and not as a part of her duties as an employee. Z.K.W. is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals Inc. (BHV4157-206) and Vigil Neuroscience Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for Vigil Neuroscience Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. F.K. received personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, Sanofi, Teva, Vial, and the Austrian Society of Neurology in the past 12 months, and he has ongoing grant support from the Austrian Science Fund (FWF) and the National Institutes of Health outside of the submitted work. W.G.M. has received fees for editorial activities with Elsevier and has served as an advisor for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase, Takeda, and Teva., (Published by Elsevier Inc.)

Background: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS)., Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available., Results: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management., Conclusions: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed., (Copyright © 2024. Published by Elsevier Inc.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)